Package for a pharmaceutical product and method of sterilizing the package

ABSTRACT

A package for a pharmaceutical product, particularly a liquid ophthalmic composition, such as an ophthalmic solution, gel or ointment, for example a tube or a dropper bottle assembly used to dispense said product, wherein said package is made of a specific form of polypropylene and wherein said package shows after an autoclaving processing of at least 121° C. and for at least 20 minutes no deformation such as shrinkage or blowing-up and retains a sufficient high squeezability in order to dispense said product. Also claimed is a method for sterilizing a pharmaceutical package comprising the steps: placing closed package into an autoclaving chamber, adjusting the temperature and the pressure in said chamber as a function of time in accordance to the prerequisites of the material of said package, wherein a counter pressure is generated in said chamber and wherein this is regulated electronically via computer, and wherein said counter pressure avoids a deformation such as a blowing-up of said package.

[0001] The invention relates to a package for a pharmaceutical product,particularly a tube or a dropper bottle assembly used to dispenseliquids, aerosols or strings, and a method of sterilizing said package.

[0002] Particularly dropper bottle assemblies are used to dispense avariety of liquids, typically one drop at a time. For example, thedispensing of a liquid reagent used in laboratories, dispensing eyemedication, dispensing ear medication, dispensing nose medication, or inany other environment where dispensing of a liquid in controlled dropincrements is desired.

[0003] A typical prior art bottle assembly comprises a plastic squeezebottle, a nozzle tip or dropper which is snap fit into the bottle and acap or closure which is threaded onto the bottle. Liquid is dispensedone drop at a time by squeezing the bottle so as to force liquid out theend of the nozzle tip. The bottle, the nozzle tip and the cap are madeof low density polyethylene because this material has a high enoughmodulus of elasticity for squeezing the cylindrical sidewall of thebottle with one's fingers which causes the liquid therein to passthrough a passageway.

[0004] For filling the bottle with a pharmaceutical product,particularly an ophthalmic liquid which has to fulfill the conditionsconcerning sterility, it is state of the art to filtrate and tosterilize the solution or liquid which should be filled into the bottlesby filtration or autoclaving. Also the bottles, the nozzle tips and thecaps are sterilized, e.g. by ethylene oxide treatment, UV, gamma orelectron beam irradiation. The filling of the bottles takes place inaseptic room conditions. However, after filling the bottles, insertingthe nozzle tip into the neck portion and threading the cap onto thebottle no further sterilization will proceed. The filled and closedbottles are removed from the aseptic area. The aseptic area is normallya room which stands under slight excess air pressure and the entranceand the exit of the room are constructed as sluices.

[0005] A pharmaceutical product as used hereinbefore or hereinafter isunderstood to relate in particular to a pharmaceutical composition,which is preferably an aqueous and/or a non-aqueous pharmaceuticalcomposition or a mixture of a non-aqueous and an aqueous pharmaceuticalcomposition, which is preferably a liquid solution, a gel or anointment, wherein pharmaceutical relates preferably to an ophthalmic, anotic and/or a nasal administration.

[0006] However, the standard method of filling bottles withpharmaceutical substances, particularly with ophthalmic solutions andgels does not fulfill the European Pharmacopoeia, 3rd. edition (1997)e.g. page 283, and/or the EU regulation (Committee of ProprietoryMedicinal Products [CPMP], Section 5, Manufacturing Process, Note forGuidance). According to this regulation, an ophthalmic pharmaceuticalliquid or gel should be terminally sterilized in their final containerfor achieving the highest level of sterility assurance, if everpossible. But using for sterilization an autoclaving method with atemperature of at least 121° C. for at least 15 minutes for the lowdensity polyethylene bottles known in the prior art deformation, e.g.shrinkage or blowing up occur and the bottles have lost their elasticityso that they are damaged or partly molten and not squeezable anymore.

[0007] The invention addresses the problem of providing a pharmaceuticalpackage, particularly a bottle assembly or a tube filled with apharmaceutical product, particularly an ophthalmic solution or gel,meets the requirements of the European Pharmacopoeia regulation and/orEU-regulation without any significant deformation and retaining asufficient squeezibility for dispensing the liquid after the autoclavingproceedings.

[0008] The invention solves this problem with the features indicated inboth claims 1 and 10. With regard to further substantial designfeatures, reference is made to the dependent claims.

[0009] The use of a specific form of polypropylene for the material ofthe package enables to fulfill the European Pharmacopoeia regulationand/or EU regulation. Packages made of a specific form of polypropyleneare heat-resistant and retain their formation and their squeezingcharacteristics after the autoclaving processing. Therefore, theconsumer can easily dispense one drop at a time by squeezing the packageso as to force the pharmaceutical product out of the package.Particularly the invention provides a tube or a dropper bottle assemblywith a high enough squeezibility for dispensing an ophthalmic solutionor gel by compressing the tube or bottle.

[0010] Further details and advantages of the invention are apparent fromthe following description and drawings. The drawings show:

[0011]FIG. 2 a front view of a dropper bottle assembly as an example ofthe invention;

[0012]FIG. 2 a front view, partially in cross section of a dropperbottle assembly in FIG. 1;

[0013]FIG. 3 a diagram of the temperature and the pressure run in theautoclaving chamber during the autoclaving processing for a 5 ml bottle;

[0014]FIG. 4 a diagram of the temperature and the pressure run in theautoclaving chamber during the autoclaving processing for a 10 mlbottle;

[0015]FIG. 5 a test diagram which shows the power as a function of theelasticity for a 5 ml bottle;

[0016]FIG. 6 a test diagram which shows the power as a function of theelasticity for a 10 ml bottle.

[0017] Referring to FIGS. 1 and 2, there is illustrated as an example ofthe invention a dropper bottle assembly 1 which comprises a squeezebottle 2 having a nozzle tip 3 designed to snap fit within the neckportion 4 of the bottle 2, and a cap 5 designed to fit over the nozzletip 3 and engage threaded portion 6 of the neck portion 4. The nozzletip 3 has a passageway 7 for allowing fluid within the bottle 2 to bedispensed through outlet 8. Liquid is dispensed by first removing cap 5and then squeezing the cylindrical sidewall 9 of bottle 2 with one'sfingers which causes the liquid therein to pass through a passageway 7.For safety purposes the bottle assembly is further provided with eithera shrink collar or with a temper resistance ring 10.

[0018] The bottle 2 is made of a specific form of polypropylene,particularly a polypropylene of the type Appryl 3020 SM 3. In comparisonwith the prior art the bottle 2 has a similar shape with the exceptionthat the bottom 12 has advantageously a concave configuration. This isin particular for avoiding deformation, e.g. shrinkage or blowing-up, ofthe bottle during the autoclaving processing. Due to the concaveconfiguration the degree of pressure necessary to cause deformation ofthe bottom is much higher. Naturally, other indentation, grooves, slitsor slots can be designed at the bottom 12 or the sidewall 9 to give thebottle 2 a greater stability during the autoclaving processing. Thenozzle tip 3 is also particularly formed of a specific form ofpolypropylene, particularly a polypropylene of the type Appryl 3020 SM3. There occur no problems during the autoclaving processing which couldgenerate leakage problems. Rather, by using the same material for thebottle 3 and the nozzle tip 3 the two components are sealed a little bittogether during the autoclaving processing. Furthermore, aspolypropylene is a quite rigid material and it is more difficult to snapfit the nozzle tip 3 into the neck portion 4 of the bottle 2, the nozzletip 3 has a special configuration to ensure a good seal between thebottle 2 and the nozzle tip 3. The sealing part 13 of the nozzle tip 3used for sticking the nozzle tip 3 into the neck portion 4 of the bottle2 is formed in the upper part nearly cylindrical whereas the lower parthas the form of a taper shank. As a stopping face the sealing part 13 ofthe nozzle tip 3 is provided with a collar 14. The cap 5 is threaded onthe neck portion 4 of the bottle 2 having external threads 6. The cap 5as the closure of the bottle assembly is particularly formed of a highdensity polyethylene, particularly of HDPE GC 7260. The cap 5 can alsobe made of polypropylene, however in this case during the autoclavingprocessing a sealing between the nozzle tip 3 and the cap 5 can occur,so that it is quite difficult to open the bottle 2 or the nozzle tip 3is damaged after opening of the bottle 2. If the cap 5 is made ofanother material than polypropylene, particularly of high densitypolyethylene, the risk of a sealing or other damages can be avoided asthese two materials have a different modulus of elasticity.

[0019] The wall thickness of the PP bottle is typically in the range of0.3 mm to 0.6 mm, preferably 0.45 mm. If the wall thickness is too thin,then the stability of the bottle decreases. However, if the wallthickness is too thick, then the squeezability of the bottle decreasesand the bottle becomes too rigid. Indeed, the preferable value of thewall thickness is lower than in comparison with the prior art PEbottles, so that there is much lesser material necessary for molding thebottles, preferably by an injection molding process.

[0020] When the package of the present invention relates to a tube, thematerial may also be a so-called laminated PP-foil (polyfoil tube)exhibiting a sandwich-type structure. Typically such a laminated foilcontain one or more layers of polypropylene (PP), preferably two (e.g. atop and a bottom layer), and one or more layers of aluminum, preferablyone (e.g. the middle layer). Said laminated material provides typicallyenhanced stability.

[0021] Further, it is advantageous to adjust the autoclaving processingto the PP-bottles to avoid damages as shrinkage or blowing-up. Afterfilling the bottles with the pharmaceutical liquid or gel, particularlyan ophthalmic liquid or gel, the closed bottles are introduced into anautoclaving chamber. In the context of the present application fillingof the bottles denotes typically a normal filling, such that for examplein the upper part of said bottle some air will remain. As the wholebottles will be sterilized it is not anymore necessary that the fillingand closing of the bottles has to take place under aseptic conditions.As it is known in the prior art, such an autoclaving chamber works withsteam. The temperature and the pressure run in the chamber as a functionof time is demonstrated in FIGS. 3 and 4. The chamber contains typicallyone or more nozzles for the steam entrance and typically several sensorsfor temperature monitoring. Advantageously the temperature can beadjusted very quickly if some corrections might be necessary.

[0022] Further, particularly the chamber is provided with a pressuredevice for generating a counter pressure in the autoclaving chamber.Also the pressure can be adjusted very quickly if some corrections mightbe necessary. Preferably, the counter pressure is regulatedelectronically via computer control. Said pressure set-up isadvantageously used for avoiding a blowing-up of the bottles. Afterintroducing the bottles into the chamber, the temperature risestypically from room temperature to 121° C. and the pressure risestypically from atmospheric pressure to a maximum value which ischaracteristic for the sterilization process. Typically, the choice ofthe pressure value depends on the form of the bottles.

[0023]FIG. 4 shows in an exemplary fashion the adjusted pressure with avalue of 2700 mbar is lower for the 5 ml bottles than for the 10 mlbottles with a value of 3200 mbar. As the 5 ml bottles are more rigid incomparison to the 10 ml bottles a lower pressure value is necessary toavoid blowing up of the bottles. In the beginning of the autoclavingprocess the increasing of the temperature is quite steep, whereas thegradient of the pressure remains nearly constant up to reaching themaximum value. During the sterilization the values of the temperatureand the pressure maintain constant. After the sterilization both thetemperature and the pressure decreases continuously. The autoclavingprocessing takes as a whole nearly one hour. After reaching again roomtemperature and atmospheric pressure the chamber will be opened fortaking out the sterilized bottles.

[0024] Several test programs have shown that after an autoclavingprocedure of a temperature of 121° C. during 20 minutes with anautoclaving procedure according to the above described diagrams nodeformation, e.g. shrinkage or blowing-up of the PP bottle assemblycould be observed. Two diagrams demonstrating the squeezability of abottle assembly with a volume of 5 ml and of 10 ml are shown in FIG. 5and FIG. 6. To achieve typically a compression of 2 mm in comparison tothe normal dimension of the bottle, typically a power value of about 9 Nis necessary for a 5 ml PP-bottle. For a 10 ml PP bottle, typically apower value of about 14 N is required. For comparative purposes itshould be mentioned that prior art PE bottles exhibit typically asimilar squeezability, e.g. the 5 ml PE bottle slightly less, the 10 mlPE-bottles a little bit more power. For the consumer these values arevirtually equivalent.

[0025] Further tests concerning the tightness of the bottles before andafter the autoclaving procedure show compliance with the regulations forpharmaceuticals. Tests concerning the O₂-barrier and the H₂O-barrierproperties of the bottles in accordance to the invention (despite ofthinner walls) after stress storage during 4 weeks at 80° C. show nodifference to the PE-bottles known from the prior art. Furthermore,tests in respect to bacteria toxicity show that no toxicity could bedemonstrated for the PP-bottles. PE-bottles known from the prior art aretypically twice as thick as the PP-package (PP-bottles) of the presentinvention.

[0026] Therefore, the invention provides a package particularly a tubeor a dropper bottle assembly for pharmaceutical products, especially forophthalmic pharmaceutical solutions and gels which can be sterilized asa whole after filling the product into the package by an autoclavingprocess in accordance to the invention. The package retains after theautoclaving procedure its squeezability which is important for theconsumer for dispensing especially a solution or gel out of the package.Furthermore, no deformation could be observed after having exposed saidpackage to an autoclaving process in accordance to the invention. Thismeans that a package according to the invention, especially a dropperbottle assembly filled with an ophthalmic solution, gel or ointment,fulfills the European Pharmacopoeia, 3rd. edition (1997), and/or the EUregulation mentioned above, which ensure a higher level of safety.

[0027] In addition, the PP-material used for fabricating the package inaccordance to the invention exhibits physical chemical properties whichmeet the requirements laid down in the supplement of 1998 of theEuropean Pharmacopoeia, 3rd edition (1997). This is in particularapplicable to the additives comprised in the PP-material in accordanceto the invention.

1. A package for a pharmaceutical product, particularly a liquidophthalmic composition, such as an ophthalmic solution, gel or ointment,for example a tube or a dropper bottle assembly used to dispense saidproduct, wherein said package is made of a specific form ofpolypropylene and wherein said package shows after an autoclavingprocessing of at least 121° C. and for at least 20 minutes nodeformation such as shrinkage or blowing-up and retains a sufficienthigh squeezability in order to dispense said product.
 2. A packageaccording to claim 1, wherein said package meets the requirements of theEuropean Pharmacopoeia, 3rd. edition (1997) and the EU-regulation. 3.Package of claim 1 or 2, wherein said package comprises a plastic bottle(2) for holding said product to be dispensed, a plastic nozzle tip (3)for dispensing said product and a cap (5) for closing said bottle.
 4. Apackage according to claim 3, wherein said bottle (2) having a neckportion (4) that includes an externally threaded portion (15) and anouter rim which defines an outlet of the bottle, and said nozzle tip (3)being in fluid contact with said outlet of said bottle and having andispensing passageway (7) for allowing liquid within said bottle (2) topass out of an outlet (8) of said nozzle tip (3), and said cap (5)having internal threads for engagement with said externally threadedportion (15) of said neck portion (4).
 5. A package according to claim3-4, wherein said bottle (2) is made of a specific form ofpolypropylene, the nozzle tip (3) is made of a specific form ofpolypropylene and the cap (5) is made of a specific form ofpolypropylene and/or of high density polyethylene.
 6. A packageaccording to claim 3-5, wherein said bottle (2) is made of Appryl 3020SM 3, the nozzle Up (3) is made of Appryl 3020 SM 3, and the cap (5) ismade of HDPE GC 7260 or of polypropylene.
 7. A package according to anyof claims 3 to 6, wherein the bottom (12) of the bottle (2) has aconcave configuration.
 8. A package according to any of claims 1 to 7,wherein the wall thickness of the package, particularly the bottle (2)is in the range of 0.3 mm to 0.6 mm.
 9. A package according to any ofclaims 1 to 8, wherein the wall thickness of the package, particularlythe bottle (2) is 0.45 mm.
 10. Method for sterilizing a pharmaceuticalpackage comprising the steps, placing closed package into an autoclavingchamber, adjusting the temperature and the pressure in said chamber as afunction of time in accordance to the prerequisites of the material ofsaid package, wherein a counter pressure is generated in said chamberand wherein this is regulated electronically via computer control, andwherein said counter pressure avoids a deformation such as a blowing-upof said package.
 11. Method of claim 10, wherein the pressure value isadjusted to the size of the packages to be sterilized.
 12. Method ofclaim 10, wherein the pressure value is adjusted to the type ofpolypropylene.
 13. Method of claim 10, wherein said package is a bottle,more preferably a PP-bottle.
 14. Package of claims 5-9, wherein thephysical chemical properties of said polypropylene meet the requirementslaid down in the supplement of 1998 of the European Pharmacopoeia, 3rdedition (1997).
 15. (New) A package for a pharmaceutical product whereinsaid package is made of polypropylene and wherein said package, afterautoclaving at at least 121° C. and for at least 20 minutes, suffers nodeformation, does not shrink, and does not explode, and wherein saidpackage retains a sufficiently high squeezability to dispense saidproduct.
 16. (New) A package according to claim 15, wherein said packagemeets the requirements of the European Pharmacopoeia, 3rd edition (1997)and the European Union regulation.
 17. (New) A package according toclaim 15 wherein said package comprises a plastic bottle for holdingsaid product to be dispensed, a plastic nozzle tip for dispensing saidproduct, and a cap for closing said bottle, wherein said bottle haswalls that have a wall-thickness.
 18. (New) A package according to claim17, wherein said bottle comprises a neck portion that includes anexternally threaded portion and an outer rim which defines an outlet ofthe bottle, wherein said nozzle tip is in fluid contact with said outletof said bottle and wherein said nozzle tip has a dispensing pathway influid communication with an outlet, and wherein said cap has internalthreads for engagement with said externally threaded portion of saidneck portion of said bottle.
 19. (New) A package according to claim 17,wherein said bottle is made of Appryl 3020 SM 3, the nozzle tip is madeof Appryl 3020 SM 3, and the cap is made of HDPE GC 7260 or of lowdensity polyethylene.
 20. (New) A package according to claim 17, whereinsaid bottle has a bottom portion, and said bottom portion of said bottlehas a concave configuration.
 21. (New) A package according to claim 17,wherein said bottle has a wall-thickness in the range of 0.3 mm to 0.6mm.
 22. (New) A package according to claim 21, wherein saidwall-thickness is 0.45 mm.
 23. (New) A package of claim 17, wherein thephysical chemical properties of said polypropylene meet the requirementslaid down in the supplement of 1998 of the European Pharmacopoeia,3^(rd) edition (1997).
 24. (New) A package of claim 19, wherein thephysical chemical properties of said polypropylene meet the requirementslaid down in the supplement of 1998 of the European Pharmacopoeia,3^(rd) edition (1997).